Post on 20-Feb-2021
Psychomotorstimulants(psychostimulants)
Timár Júlia
2020
cocaine
Amphetamines (AMs)
stimulant
amphetamine,
methamphetamine,
methylphenidate,
katine,
MDMA (ecstasy),
etc.
stimulant +
hallucinogenic
mescaline,
DOM,
MDA,
MDMA (high dose),
etc.
PSYCHOSTIMULANTS
CA transmission5-HT transmission
NE
in the periphery
increase of
sympathetic tone
DA
in the brain
stimulant
effect
hallucination
dependence
MECHANISM of ACTION
amphetamines
cocaine
mesolimbic-mesocortical
pathway
Figure from Koob, Focus, 2011, originally adapted from Nestler, Nat Neurosci, 2005
indirectly activate the dopamine transmission
MECHANISM of ACTION of COCAINE and ATS
Binding to DAT - inhibition of reuptake
MECHANISM of ACTION of COCAINE
reverse transport
MECHANISM of ACTION of ATS
Amphetamine enhances mainly the DA release, but
other derivatives (Methamphetamine, MDMA) influence
the NA and the 5-HT release, too
Further effect of AMs:
MAO inhibition
inhibition of transmitter reuptake
Cocaine inhibits mainly the DA reuptake, but influences
the NA and 5-HT reuptake as well
MECHANISM of ACTION II
well being
euphoria - ”rash”, „high”
increase of physical abilities
increase of mental capacity (controversial)
effect depends on dose
route of administration
first or repeated
administration
accompanying
circumstances
EFFECTS of PSYCHOSTIMULANTS
Time (min)
10 20 30 40 50 60 120
eff
ect
0
200
400
600
800
1000
1200
1400
1600
1800
2000
THE INTENSITY AND TIME COURSE OF COCAINE
INTOXICATION
DEPENDENCE POTENTIAL
Stimulants
cocaine very strong
amphetamines strong
DRUGS of ABUSE
dep
en
den
ce
physical damage
Infusion
pumpProgramming and
recording equipment
catheter
lever
SELF-ADMINISTRATION
positive
equal unequal
continuous
increase
no
increasefrequent not frequent
Morphine
Meperidine
Codeine
Pentazocine
Alcohol*
Nicotine
Diazepam
Chlordiaze-
poxide
Cocaine
Amphetamines
Inhaled
anesthetics
THC
Caffeine
* Only alcohol preferring strains
SELF-ADMINISTRATION
Psychic Physical Tolerance
Drug Dependence
Morphine & Derivatives +++ +++ +++
Amphetamine-like ++ (+) ++
(in case of regular use)
Cocaine +++ (+) (+)
AMPHETAMINES (ATS)
Dopamine
CH2-CH2-NH2
HO
HO
Ephedrine
CH - CH - NH - CH3
OH CH3
Phenylethylamine (PEA)
4
CH2-CH2-NH21
23
5 6
dextrorotatory form is biologically more active
Ephedra viridis,
mormon tea
Amphetamine (speed)
CH2 - CH - NH2
CH3
CH - CH - NH - CH3
OH CH3
Methamphetamine (speed in
U.S.A.)
CH2 - CH - NH - CH3
CH3
H2CCH2 - CH - NH - CH3
O
O CH3
CH2 - CH - NH2O
CH3H2C O
Methylenedioxyamphetamine
(MDA)
Methylendioxy-methamphetamine
(MDMA, „ecstasy”, Adam, E,
essence)
Ephedrine
MDA (DOM, etc.) - hallucinogenic AM
methylcathinone
CH - CH - NH - CH3
O CH3
cathinone
CH - CH – NH2
O CH3
Alkaloid of Khat (Catha edulis)
Mephedrone (4MMC)
Very toxic
tolerance quick
aggression
toxic metabolites
Designer drug
Methylone, MDPV (Methylene-dixypyrovaleron)
Benzofury, 4Mec (amphetamine group)
MDAI 5,6-Methyilene-dioxy-2 aminoindan
4-Fa 4-fluoroaphfetamine
Stimulants (amphetamine-like)
„DESIGNER” DRUGS I
Designer drugs are structural or functional analogs of controlled
substances that has been designed to mimic the pharmacological
effects of the original drug, while avoiding classification as illegal
Psychoactive substances
Performance enhancing drugs (designer steroids)
Dimethocaine larocaine (local anesthetic, about half as potent as
cocaine)- used to be used in UK and Ireland
http://legal-drog.info/methylone.htmlhttp://legal-drog.info/mdpv-furdoso.htmlhttp://legal-drog.info/benzofury.htmlhttp://legal-drog.info/4mec-rendeles-formek-hatasa.htmlhttp://legal-drog.info/mdai-hatasai-rendeles-adagolasa.htmlhttp://legal-drog.info/4-fa-hatasai-adagolasa-rendeles.htmlhttp://legal-drog.info/dimethocaine-rendeles-hatasai.html
Other Chat derivatives
3-Methylmethcathinone (3MMC)
4-Methylethcathinone (4MEC)
Pentedrone (α-methylamino-valerophenone)
penta crystal – cocaine-like effect
butil
„DESIGNER” DRUGS II
MPDV and derivatives
alpha-pyrrolidinopentiophenone (α-PVP)
MPDV (methylenedioxypyrovalerone)
alpha-pyrrolidinohexiophenone (α-PHP)
Pentedrone
pyrrolidine
„DESIGNER” DRUGS III
Bath salt
https://image.slidesharecdn.com/designerdrugspringupdatebklwebinarmay2012-120525134751-
phpapp02/95/trends-report-on-changes-in-the-designer-drug-market-spring-2012-29-728.jpg?cb=1337954029
2012
2010 2011 2012 2013 2014
1 THC THC THC THC THC
2 amfetamin amfetamin pentedron AKB-48F *
(apinaca)
AB-
CHMINACA*
3 mefedron 4-MEC AM-2201* pentedron amfetamin
4 kokain MDVP amfetamin amfetamin MDMB-
CHMICA *
MDVP (10) Mefedron (8) Kokain (8)
4-MEC (9)
3-MMC (6)
Α-PVP (8)
MDMA (9)
Mefedron (10)
Pentedron (5)
Α-PVP (7))
MDMA (9)
Csesztregi Tamás Bűnügyi Szakértői és KutatóintézetSzerves Kémiai Analitikai Szakértői Osztály
Confiscated and determined drugs in
Hungary
Rush ( ~ orgasm like reaction; sex drive is enhanced)
Subjects become confident, hyperactive,
talkative (MDMA – entactogen – „touching
within”)
Mental alertness
Fatigue physical
mental
is reduced
(military persons, pilots, students - exams ??)
Exhaustion (lack of sleep, food)
ATS EUPHORIA
Increased motor activity
Euphoria and excitement
lasts for a few hours, and is
followed
by depression and anxiety
EFFECT of AMPHETAMINES
Anorexia
With prolonged administration psychotic behaviour
Tolerance to the stimulant effects develops rapidly, though peripheral sympathomimetic effects may persist
rested, at ease and
mentally alert
drowsy, bored or
tired
anxiety
irritability
alertness
euphoria
increased vigour
mental/physical
abilities are increased
amphetamines
produce
In subjects who are
narcolepsy
attention deficit hyperkinetic syndrome (methylphenidate)
they used to be used (e.g. dexfenfluramine) as appetite-suppressants
Therapeutically used amphetamine derivative is METHYLPFENIDATE(low abuse potential)
THERAPEUTICAL APPLY of ATS
Clinical aspects induced by ATS:
acute intoxication
withdrawal
Central nervous system
agitation convulsions muscle rigidity hyperthermia sweating
dehydration/orwater poisoning
(hyponatremia)hallucinations
panicdilated pupils coma
Cardiovascular system
tachycardiaventricular
arrhythmiashypertension
followedby hypotension
spontaneous bleeding
stroke
TOXIC EFFECTS of ATS I
Renal system
oliguria; myoglobinuria
kidney failure
Gastrointestinal system jaundice; hepatomegaly
Laboratory tests metabolic acidosis; hyperkalemia;raised creatinine, creatine
phosphokinase, impaired liver function tests; hypoglycemia
Hematology disseminated intravascular coagulation (DIC)
(thrombocytopenia,abnormal coagulation profile,
low fibrinogen)
TOXIC EFFECTS of ATS II
supportive therapy
ventilation, gastric lavage with charcoal
agitation /convulsions: diazepam
hypotension: fluid therapy, inotropic support
temperature control: over 42o C no survival !!!!
cooling blankets, ice packs, infusion of cold
saline etc.
neuromuscular blockade: dantrolene
(inhibits Ca++ release from SR )
TREATMENT of MDMA INTOXICATION
supportive therapy (cont.):
metabolic acidosis – precipitating cardiac arrhythmias
sodium bicarbonate
DIC: with severe bleeding – replacement of clotting
factors
specific therapy ???
selective 5-HT2 receptor antagonist: ketanserin
chlormethiazole: attenuates thermogenesis given
before MDMA (rat)
TREATMENT of MDMA INTOXICATION
Tolerance can develop to
euphoria
anorexia
hyperthermia
acute lethal effects
anorexia ketosis acidic urine increased elimination
Sensitization can develop to
amphetamine psychosis can develop even after
one dose
(high individual differences)
REPEATED ATS
Instrumental usage – usage in order to attain something (e.g.
improve the concentration, overcome some fatigue)
Recreational (subcultural) usage
Chronic usage
CHARACTERISTIC USES of ATS
MOUTH and SKIN LESIONS in REPEATED MA
USERS
„Meth mouth”
Enhanced dental decay,
dry mouth – gingival disorders
Skin symptoms
unnaturally grey and leathery skin (melanin content
changes)
acne sores – obsessive picking of the skin
(hallucination – feeling of bugs)
weeping sores and open wounds (debilitated immune
system)
http://api.viglink.com/api/click?format=go&jsonp=vglnk_14240187545158&key=2a0252288c0abed1a28d90906ab0efe9&libId=6ef1edc4-d7e7-4aa7-bb8d-c5836aa2a669&loc=http%3A%2F%2Facnspanish.info%2Fthe%2Fthe-effects-of-drug-abuse.html&v=1&out=http%3A%2F%2Fcdn.bitrebels.netdna-cdn.com%2Fwp-content%2Fuploads%2F2011%2F03%2FEffects-of-Drug-Abuse-3.jpg&ref=http%3A%2F%2Fwww.google.hu%2Furl%3Furl%3Dhttp%3A%2F%2Facnspanish.info%2Fthe%2Fthe-effects-of-drug-abuse.html%26rct%3Dj%26frm%3D1%26q%3D%26esrc%3Ds%26sa%3DU%26ei%3DDc3gVNfhGsPyUPTtgJgP%26ved%3D0CCUQ9QEwBw%26sig2%3D4tbT6_OSb-y0wo_MPnOWHQ%26usg%3DAFQjCNGvDdw7q-86-_S7OtIEQmDjNM8e5Q&title=The%20Effects%20Of%20Drug%20Abuse%20%7C%20Women%20Health&txt=%3CIMG%20alt%3D%22Crystal%20Meth%22%20src%3D%22http%3A%2F%2Fcdn.bitrebels.netdna-cdn.com%2Fwp-content%2Fuploads%2F2011%2F03%2FEffects-of-Drug-Abuse-3.jpg%22%3Ehttp://api.viglink.com/api/click?format=go&jsonp=vglnk_14240187545158&key=2a0252288c0abed1a28d90906ab0efe9&libId=6ef1edc4-d7e7-4aa7-bb8d-c5836aa2a669&loc=http%3A%2F%2Facnspanish.info%2Fthe%2Fthe-effects-of-drug-abuse.html&v=1&out=http%3A%2F%2Fcdn.bitrebels.netdna-cdn.com%2Fwp-content%2Fuploads%2F2011%2F03%2FEffects-of-Drug-Abuse-3.jpg&ref=http%3A%2F%2Fwww.google.hu%2Furl%3Furl%3Dhttp%3A%2F%2Facnspanish.info%2Fthe%2Fthe-effects-of-drug-abuse.html%26rct%3Dj%26frm%3D1%26q%3D%26esrc%3Ds%26sa%3DU%26ei%3DDc3gVNfhGsPyUPTtgJgP%26ved%3D0CCUQ9QEwBw%26sig2%3D4tbT6_OSb-y0wo_MPnOWHQ%26usg%3DAFQjCNGvDdw7q-86-_S7OtIEQmDjNM8e5Q&title=The%20Effects%20Of%20Drug%20Abuse%20%7C%20Women%20Health&txt=%3CIMG%20alt%3D%22Crystal%20Meth%22%20src%3D%22http%3A%2F%2Fcdn.bitrebels.netdna-cdn.com%2Fwp-content%2Fuploads%2F2011%2F03%2FEffects-of-Drug-Abuse-3.jpg%22%3E
long, restless sleeping
extreme fatigues
insomnia/hypersomnia
marked appetite
psychomotor hindrance/agitation
drug seeking behaviour
depression
WITHDRAWAL SYMPTOMS
depression
risk of committing suicide
aggressive behaviour
impairment of cognitive function
is more marked than with amphetamine
(5-HT-erg effect?)
FOLLOWING REPEATED METHAMPHETAMINE or
MDMA ABUSE
Parrott AC, Lasky J (1998) Psychopharmacology, 139, 261
NORMAL UNDER ECSTASY
stimulated mood
euphoria
AFTER ECSTASY
depression
anxiety
serotonin transzporterecstasy
serotonin receptor
serotonin
ROLE of 5-HT in THE EFFECT of MDMA
Amphetamine i.v.; orally
Methamphetamine i.v.; orally; inhaled
Methamphetamine initial dose 20-40 mg
MDMA initial dose 50-100 mg
MDMA orally (generally)
t1/2 amphetamine ~ 10h
methamphetamine, MDMA ~ 5h
ROUTES of ADMINISTRATIONS
oral MDMA usage onset 20-60 min;
peak 60-90 min
demethylation by CYP2D6
poor metabolizers (7-8%)
risk of toxicity increases
METABOLISM of MDMA
CYP2D6 enzyme function is inhibited by SSRI-s (fluoxetine, paroxitene etc.) and antipsychotics
Perinatal mortality
Infant mortality
Major malformations
Birth weight < 2500 g
Gestational age< 37 weeks
Transfer to neonatal unit
5.6
5.8
3
18
20
38
1.04
0.83
1.64
4.6
5.65
10
Study group
(Sweden)
Control group
PERINATAL OUTCOME in INFANTS WHOSE
MOTHERS USED AMPHETAMINE DURING
PREGNANCY
Methamphetamine, MDMA abuse
is frequent together with
cannabis (70-80%?)
benzodiazepines (40-50%)
is rare together with heroin
Dark-field photomicrograph, sagittal plane, of 5-HT immunoreactive
axons in the caudate nucleus of a control monkey (A), a 2 week
MDMA-treated monkey (B). Scale bar, 100 µm.
(Hatzidimitriou G et al, (1992)
Dark-field photomicrograph, sagittal plane, of 5-HT immunoreactive
axons in the caudate nucleus of a control monkey (A), a 2 week MDMA-
treated monkey (B), and a 7 year MDMA-treated monkey (C). Scale bar, 100 µm.
(Hatzidimitriou G et al, (1999) J. of Neurosci. 19, 5096)
DECREASED DA ACTIVITY
red - high DA receptor level
yellow – low DA receptor level
COCA plant
PSYCHOSTIMULANTS II
free base „crack”by alkalization and
extraction
hydrophilic, white powder
„coke”, „gold dust”, „lady”
insoluble, very lipophilic
COCAINE
CH2CH2 CH
H3COOC
CH CH2
-C-O-CH N-CH3
CH
HCl
=O
●
pla
sm
a l
evel
ng
/ml
0
200
400
600
800
1000
1200
1400
1600
1800
2000
chewing sniffing smoking i.v.
crack
COCAINE – ROUTES of ADMINISTRATION
10 20 30 40 50 60None
Cocaine
„high”
Maximum
120Time (min)
THE INTENSITY AND TIME COURSE OF COCAINE
INTOXICATION
TACHYPHYLAXIS (COCAINE)
monkey, self-administrationBy Robert Mathias NIDA Notes Vol 16, No 3, 2001
SENSITIZATION (COCAINE)
cocaine (0.5 mg/kg), monkeyBy Robert Mathias NIDA Notes Vol 16, No 3, 2001
perc
enta
ge incre
ase
in e
xtr
ace
llula
r D
A
cocaine crack is especially dangerous !!!
psychic dependence +++
physical dependence (+)
tolerance ++ (in case of repeated apply with short interval)
COCAINE „SUPERAMPHETAMINE”
red - high DA receptor level
yellow – low DA receptor level
t1/2 ~ 50 min
route of administration onset of action
i.v. 1-2 min
intranasal „rush”
crack some min
cocaine HCl 30-40 min
oral 60 min
distribution into the brain is very quick
redistribution is also very quick
i.v. cocaine or crack might be repeated after 30-40 min
(quickly developing dependence)
PHARMACOKINETICS of COCAINE
Main metabolites benzoilecgonine
ecgonine methylesther
Metabolizing enzyme - cholinesterase
reduced serum cholinesterase activity in
fetus
small children
pregnant women
elder people
hepatic failure
genetic cholinesterase deficiency
METABOLISM of COCAINE I.
Elimination via kidney
detectable for 24-36 hours
via sweat
detectable for weeks
in the hair
detectable for years!
METABOLISM of COCAINE II.
• COLLAPSE of CIRCULATION arrhytmiaischemia myocardial infarctseizuresstroke
• MIGRAINE• HYPERTHERMIA• RESPIRATORY DEPRESSION
• CENTRAL SYMPTOMS anxiety
paranoia
fear of death
POSSIBLE LETHAL OUTCOME
within 2-3 hours
COCAINE OVERDOSE
nose - bleeding
headache
exhaustion/depression
hoarseness
cardiovascular problems
SYNDROME of
DIAGNOSTIC
VALUE
Treatment: cardiac arrest - epinephrine
arrhytmia – lidocaine
diazepam
Not to give beta-blockers (coronary spasm risk !)
COCAINE OVERDOSE
//upload.wikimedia.org/wikipedia/commons/d/dc/Side_effects_of_chronic_use_of_Cocaine.png//upload.wikimedia.org/wikipedia/commons/d/dc/Side_effects_of_chronic_use_of_Cocaine.png
i.v. usage
endocarditis, hepatitis, AIDS,
thrombophlebitis
SPECIAL TOXIC EFFECTS of COCAINE
intranasal usage
rhinitis, nasal bleeding, septum perforation,
spontaneous pseudomediastinum
oral usage
GI ischaemia
Characteristic symptoms of cocaine smokers
nasal bleeding
chronic hoarseness
inflammation in the septum or
rarely perforation
vivid images
acoustic hallucinations
tactile hallucinations
Characteristics of cocaine „psychosis”
very marked craving, which gradually
decreases after a couple of day and than
ceases
exhaustion
sleepiness
depression
decrease of heart rate
COCAINE – WITHDRAWAL SYMPTOMS
birth weight is smaller
head circumference is smaller
CNS developmental disorders because of
foetal vasoconstriction
withdrawal symptoms of the newborns
trembling
sharp crying voice
sweating
COCAINE ABUSE and PREGNANCY
blockade of DA receptors (neuroleptics e.g. haloperidol)
blockade of cocaine binding site on
DA - transporter protein
replacement therapy ? DA-uptake inhibitors
(e.g. mazindol)
DA-agonists (e.g. bromocriptine)
DA-releasers (e.g. amantadine)
THERAPY of COCAINE DEPENDENCE
antidepressants (at and after withdrawal)
on the basis of common DA theory buprenorphine,
naltrexone
symptomatic therapy (e.g. i.v. diazepam; propranolol)
THERAPY of COCAINE DEPENDENCE
recently studied possibilities
disulfiram
modafinil – stimulant (indicated for narcolepsy)
lorcaserin – 5-HT2C agonist, anorectic
Cocaine abusers usually take the drug in the evening rather than
the daytime, and take it continuously over a period of several
hours
Cocaine abuse frequent with heroin
Cocaine abuse also frequent with ethanol
which might be especially dangerous
cocaine plasma cc. (~ 30%), ethanol plasma cc. (~ 10%)
coca-ethylene metabolit
its t1/2 is about double of cocaine
its effects is similar to that of cocaine,
self-administered by experimental animals
euphoria
cardiovascular effects
withdrawal dysphoria
toxicity
paranoia, agitation
COCAINE + ETHANOL